神经退行性疾病相关淀粉样蛋白的液-液相分离  

Liquid-liquid phase separation of amyloid-like proteins in neurodegenerative diseases

作　　者：罗韵怡 李艳梅[1,3,4] Yun-Yi Luo;Yan-Mei Li(Key Laboratory of Bioorganic Phosphorus Chemistry&Chemical Biology of Ministry of Education,Department of Chemistry,Tsinghua University,Beijing 100084,China;College of Life Sciences,Fujian Agriculture and Forestry University,Fuzhou 350002,China;Beijing Institute for Brain Disorders,Beijing 100069,China;Center for Synthetic and Systems Biology,Tsinghua University,Beijing 100084,China)

机构地区：[1]清华大学化学系,生命有机磷化学及化学生物学教育部重点实验室,北京100084 [2]福建农林大学生命科学学院,福州350002 [3]北京脑重大疾病研究院,北京100069 [4]清华大学合成与系统生物学研究中心,北京100084

出　　处：《科学通报》2025年第7期850-859,共10页Chinese Science Bulletin

基　　金：国家自然科学基金(92353302,22237003);国家重点研发计划(2019YFA0904200)资助。

摘　　要：神经退行性疾病是一类由于大脑和周围神经系统中的细胞与神经元死亡或功能丧失而引发的疾病,包括阿尔茨海默病(AD)、帕金森病(PD)、肌萎缩侧索硬化症(ALS)和额颞叶痴呆(FTD)等.由于神经退行性疾病的病理机制尚未被完全探明,因此缺乏有效的治疗方法.大多数神经退行性疾病具有一个共同的病理表现,即淀粉样蛋白质聚集体和包涵体的形成.在过去很长一段时间内,成核聚集被认为是蛋白质聚集体形成的主要方式.然而,近几年的研究显示,越来越多的神经退行性疾病相关淀粉样蛋白可能经历液-液相分离介导的聚集,暗示淀粉样蛋白的相行为与病理之间可能存在重要关联.本文综述几种重要的神经退行性疾病相关淀粉样蛋白的性质和相分离行为研究的最新进展,包括Aβ、Tau、α-突触核蛋白、TDP-43和SOD1等.希望有助于加深人们对于神经退行性疾病相关蛋白病理机制的理解,为疾病治疗带来新的思路.Neurodegenerative diseases are diseases caused by the progressive death or loss of function of cells and neurons in the brain and peripheral nervous system,including Alzheimer’s disease(AD),Parkinson’s disease(PD),amyotrophic lateral sclerosis(ALS),and frontotemporal dementia(FTD)and others.Due to the incomplete understanding of the pathological mechanisms of neurodegenerative diseases,currently available treatment methods can only alleviate some related symptoms,and there remains a lack of effective treatment methods.Most neurodegenerative diseases share a common cellular and molecular mechanism,which is the formation of amyloid-like protein aggregates and inclusion bodies.The widespread presence of protein aggregates in neurodegenerative diseases suggests their special role in disease occurrence and progression.For a long time,nucleation and aggregation was considered as the only way for protein aggregate formation.However,recent studies suggest that these proteins may undergo another aggregation process,which is liquidliquid phase separation mediated aggregation.Phase separation is the process by which biomolecules form dynamic condensates through weak multivalent interactions.In these condensates,the biomolecule concentration is highly enriched and still maintains dynamic exchange with the external environment.Phase separation is mediated by weak multivalent interactions such as electrostatic,π-related,hydrogen bonding,and hydrophobic interactions.For specific molecules,their phase separation behavior may be mainly mediated by one or some interactions.However,interactions in living systems are more complex.There has been a lot of work looking at the types of interactions that make major contributions in various systems.These findings may help us further understand how phase separation behaviors can be altered by small perturbatians on the sequences and why naturally occurring mutations produce significant physiological and biophysical effects.Proteins that undergo phase separation in living organisms usu

关 键 词：神经退行性疾病 淀粉样蛋白 聚集 相分离 

分 类 号：R74[医药卫生—神经病学与精神病学]